PROJECT SUMMARY Synaptic plasticity presents a cellular model for learning and memory and provides a framework to study cognitive deficits in neurological disorders. Protein phosphatase 1 (PP1) is a major regulator of synaptic plasticity that acts directly on synaptic and nuclear substrates involved in synaptic plasticity, including AMPA receptors and CREB, respectively. There are three neuronal isoforms of PP1 with different but overlapping subcellular localizations and substrates. Each PP1 isoform is highly expressed in the hippocampus, but their distinct functions have not been studied. Rather, the isoforms have been grouped together in classic studies that use pharmacologic or peptide inhibition of PP1. PP1? and PP1?1 are assumed to be the primary isoforms regulating synaptic plasticity due to their enrichment in the dendritic spine and interactions with major scaffolding proteins, whereas PP1?, found primarily in the dendritic shaft and soma, is believed to play a minor role. Surprisingly, human de novo mutations were recently discovered in PP1? that cause intellectual disability and autism-like behaviors. Using a genetic knockout approach with floxed transgenic mice, I investigated the effect of knocking out individual PP1 isoforms on synaptic transmission and plasticity in the hippocampus, at Schaffer collateral-CA1. My preliminary data suggest a novel role for PP1? that opposes PP1?1, while PP1? plays a minor, redundant role. Additionally, my preliminary data demonstrates a role of PP1 in regulating basal synaptic transmission, which is otherwise obscured by classic pharmacological approaches. In this project, I will replicate and expand these findings using several approaches: electrophysiology, immunoblotting, morphological analysis, and imaging. In Aim 1, I will investigate the role of each PP1 isoform in regulating synaptic transmission and plasticity using our floxed transgenic mice, which allow for PP1 isoform-specific knockout. In Aim 2, I will determine the effect of human de novo PP1? mutations on synaptic transmission and plasticity using a genetic replacement approach, in which one copy of wildtype PP1? is replaced with mutated PP1?, as in affected human patients. Completion of this project will provide me with the knowledge base and technical skills necessary to pursue a successful career as a physician-scientist in neurology. Moreover, these findings will inform our understanding of the molecular mechanisms of synaptic plasticity and their connection to intellectual disability.